【结 构 式】 |
【分子编号】67530 【品名】4-methoxy-3-buten-2-one 【CA登记号】51731-17-0 |
【 分 子 式 】C5H8O2 【 分 子 量 】100.117 【元素组成】C 59.98% H 8.05% O 31.96% |
合成路线1
该中间体在本合成路线中的序号:(III)Chlorination of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (I) using (COCl)2 in refluxing CHCl3 gives the corresponding acid chloride (II) , which by condensation with 4-methoxy-3-buten-2-one (III) by means of LiHMDS in THF at –78 °C affords the hepta-1,4-dien-3-one derivative (IV) . Cyclization of intermediate (IV) in the presence of TFA in toluene or benzene produces the pyranone (V) (1-5), which is treated with aqueous NH3 at 65 °C to provide pyridinone (VI). Bromination of compound (VI) with POBr3 in toluene at 80 °C or in dichloroethane at 85 °C leads to the 4-bromopyridine derivative (VII). Subsequent coupling of bromopyridine (VII) with 2-acetamido-4-methylthiazole (VIII) by means of Pd(OAc)2, t-Bu3P·HBF4 and Cs2CO3 in refluxing DMF yields the pyridylthiazole adduct (IX), which by deacetylation using HCl in refluxing EtOH affords the 2-aminothiazole derivative (X) . Acylation of amine (X) with phenyl chloroformate (XI), optionally in the presence of DIEA in THF gives the thiazolylcarbamate (XII), which is finally condensed with L-prolinamide (XIII), optionally in the presence of Et3N in H2O .
Similarly, reaction of amine (X) with carbonyldiimidazole (XIV) in refluxing CH2Cl2 gives the carbamoyl imidazolide (XV), which is finally coupled with L-prolinamide (XIII) in the presence of Et3N in DMF or in DMAc at 65°C .
【1】 Furet, P., Guagnano, V., Fairhurst, R.A. et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett 2013, 23(13): 3741-8. |
【2】 Caravatti, G., Fairhurst, R.A., Furet, P., Guagnano, V., Imbach, P. (Novartis AG). Organic compounds. kR 2011038737; US 2010105711; US 8710085; CN 102149711; US 2014005232; JP 2012502080; US 8476268; US 8227462; US 2014186469; EP 2331537; WO 2010029082; CA 2734819; US 2012263712. |
【3】 Caravatti, G., Guagnano, V., Fairhurst, R. et al. Discovery of a novel 2-aminothiazole derivative (NVP-BYL719) with potent and selective PI3Kalpha inhibitory activity. 22nd Int Symp Med Chem (September 2-6, Berlin) 2012, Abst L25. |
【4】 Gallou, I.S., Gauer, C., Stowasser, F. (Novartis AG). A crystalline form of (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-(4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl)-amide and its use as PI3K inhibitor. WO 2012016970. |
【5】 Caravatti, G., Guagnano, V., Fairhurst, R. et al. 2-Aminothiazoles as potent and selective PI3Kalpha inhibitors: Discovery of NVP-BYL719 and structural basis for the isoform selectivity. 103rd Annu Meet Am Assoc Cancer Res (AACR) (March 31-April 4, Chicago) 2012, Abst 1922. |
【6】 Erb, B., Gallou, I.S., kleinbeck, F.k. (Novartis AG). Synthesis of 2-carboxamide cycloamino urea derivatives. US 2013331579; kR 2014009432; EP 2681192; JP 2014511387; CN 103402982; WO 2012117071. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 67528 | 3,3,3-trifluoro-2,2-dimethylpropanoic acid | C5H7F3O2 | 详情 | 详情 | |
(II) | 67529 | 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride | C5H6ClF3O | 详情 | 详情 | |
(III) | 67530 | 4-methoxy-3-buten-2-one | 51731-17-0 | C5H8O2 | 详情 | 详情 |
(IV) | 67531 | (1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one | C10H13F3O3 | 详情 | 详情 | |
(V) | 67532 | 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one | C9H9F3O2 | 详情 | 详情 | |
(VI) | 67533 | 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one | C9H10F3NO | 详情 | 详情 | |
(VII) | 67534 | 4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihydropyridine | C9H11BrF3N | 详情 | 详情 | |
(VIII) | 67535 | 2-acetamido-4-methylthiazole | 7336-51-8 | C6H8N2OS | 详情 | 详情 |
(IX) | 67536 | N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)acetamide | C15H16F3N3OS | 详情 | 详情 | |
(X) | 67537 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine | C13H14F3N3S | 详情 | 详情 | |
(XI) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
(XII) | 67538 | phenyl (4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate | C20H18F3N3O2S | 详情 | 详情 | |
(XIII) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
(XIV) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
(XV) | 67539 | N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-1H-imidazole-1-carboxamide | C17H16F3N5OS | 详情 | 详情 |